We propose to test the hypothesis that clonal evolution is fundamentally flawed: in the absence of genetic exchange, adaptation by natural selection indirectly drives mutation rates to catastrophic levels, and the population abruptly goes extinct a process that has been dubbed the mutation-rate catastrophe. Our proposal is motivated by the potential for deep implications in evolutionary biology and by intriguing potential for innovative applications to public health. If this subverting effect of clonality could be harnessed to eliminate troublesome microbial populations, it would be an altogether new kind of strategy: whereas adaptation by natural selection is the foremost enemy of most current anti-microbial strategies, it would be a friend to this new strategy;indeed, this strategy would be driven by adaptation, and the faster a population adapts, the more quickly it would be driven extinct. To test the mutation-rate catastrophe hypothesis, we will: 1) develop analytical theory, 2) perform large-scale in silico experiments, and 3) perform key in vitro experiments with Escherichia coli. Our time limitations leave little hope for direct in vitro observation of the mutation-rate catastrophe, but we hope to partially compensate for this short-coming through tight interaction among the three components of our investigation. Short-term, controlled in vitro experiments, for example, will provide data that will be incorporated into the more laisser-faire in silico experiments. Spontaneous occurrence of the mutation-rate catastrophe in large-scale in silico experiments that are informed by controlled in vitro experiments, should provide a compelling surrogate to direct in vitro observation. PROJECT NARRATIVE: We propose to test the hypothesis that clonal evolution is fundamentally flawed: in clonal populations, adaptation by natural selection indirectly drives mutation rates to catastrophic levels, and the population abruptly goes extinct. If such a subversion of natural selection could be harnessed to eliminate troublesome microbial populations, it would be an altogether new kind of strategy: whereas adaptation by natural selection is the foremost enemy of most current anti-microbial strategies, it is a friend to this new strategy;indeed, this strategy is driven by adaptation, and the faster a population adapts, the more quickly it is driven extinct.